ABO-compatible liver allograft antibody-mediated rejection: an update

Abstract

Purpose of review: Liver allograft antibody-mediated rejection (AMR) studies have lagged behind parallel efforts in kidney and heart because of a comparative inherent hepatic resistance to AMR. Three developments, however, have increased interest: first, solid phase antibody testing enabled more precise antibody characterization; second, increased expectations for long-term, morbidity-free survival; and third, immunosuppression minimization trials.

Recent findings: Two overlapping liver allograft AMR phenotypic expressions are beginning to emerge: acute and chronic AMR. Acute AMR usually occurs within the several weeks after transplantation and characterized clinically by donor-specific antibodies (DSA) persistence, allograft dysfunction, thrombocytopenia, and hypocomplementemia. Acute AMR appears histopathologically similar to acute AMR in other organs: diffuse microvascular endothelial cell hypertrophy, C4d deposits, neutrophilic, eosinophilic, and macrophag-mediated microvasculitis/capillaritis, along with liver-specific ductular reaction, centrilobular hepatocyte swelling, and hepatocanalicular cholestasis often combined with T-cell-mediated rejection (TCMR). Chronic AMR is less well defined, but strongly linked to serum class II DSA and associated with late-onset acute TCMR, fibrosis, chronic rejection, and decreased survival. Unlike acute AMR, chronic AMR is a slowly evolving insult with a number of potential manifestations, but most commonly appears as low-grade lymphoplasmacytic portal and perivenular inflammation accompanied by unusual fibrosis patterns and variable microvascular C4d deposition; capillaritis can be more difficult to identify than in acute AMR.

Summary: More precise DSA characterization, increasing expectations for long-term survival, and immunosuppression weaning precipitated a re-emergence of liver allograft AMR interest. Pathophysiological similarities exist between heart, kidney, and liver allografts, but liver-specific considerations may prove critical to our ultimate understanding of all solid organ AMR.

Figure 1

Typical HLA class II antigen (DR, DP, and DQ; monoclonal antibody: M0775, clone CR3/43, Dako) staining results on a tissue microarray that included normal human (A) kidney; (B) heart; and (C and D) representative portal tracts of liver. Note strong and diffuse class II expression in kidney peritubular capillaries (A) and heart interstitial capillaries (B), but absence of portal tract microvascular capillary staining (C and D). HLA class II+ cells in the liver portal tracts (C and D) are portal-based dendritic cellsIt is very difficult, if not impossible, to distinguish among portal peribiliary plexus capillaries; lymphatic capillaries; and inlet venules. (E) Elastic trichrome stain highlighting multiple squiggly elastic tissue fibers (*) scattered amongst blue-staining type 1 collagen bundles within the portal tracts; similar fibers are seen in the perivenular connective tissue surrounding larger hepatic veins (20X). (F) C4d on frozen tissue liver showing background/non-specific staining of the hepatic artery (HA) elastic lamina and wall and elastic tissue fibers (EF) within portal tracts (arrows; 20X). Abbreviations: BD: bile duct; EF: elastic fibers; HA: hepatic artery branch; PV: portal vein branch; *: portal capillary.

Figure 2

Preformed class I DSA (MFI≥5000) disproportionately affects patients transplanted with a high calculated Model for End-Stage Liver Disease (MELD) score and those who receive lower quality organs [Donor Risk Index(DRI) >1.5] when assessed in a cohort of 1270 patients from Baylor University Medical Center in Dallas from 1/00-4/09.